Interaction between the basolateral amygdala and dorsal hippocampus is critical for cocaine memory reconsolidation and subsequent drug context-induced cocaine-seeking behavior in rats.

1Department of Psychology, University of North Carolina, Chapel Hill, North Carolina 27599-3270, USA.

Abstract

Contextual stimulus control over instrumental drug-seeking behavior relies on the reconsolidation of context-response-drug associative memories into long-term memory storage following retrieval-induced destabilization. According to previous studies, the basolateral amygdala (BLA) and dorsal hippocampus (DH) regulate cocaine-related memory reconsolidation; however, it is not known whether these brain regions interact or independently control this phenomenon. To investigate this question, rats were trained to lever press for cocaine reinforcement in a distinct environmental context followed by extinction training in a different context. Rats were then briefly re-exposed to the cocaine-paired context to destabilize cocaine-related memories, or they were exposed to an unpaired context. Immediately thereafter, the rats received unilateral microinfusions of anisomycin (ANI) into the BLA plus baclofen/muscimol (B/M) into the contralateral (BLA/DH disconnection) or ipsilateral DH, or they received contralateral or ipsilateral microinfusions of vehicle. They then remained in their home cages overnight or for 21 d, followed by additional extinction training and a test of cocaine-seeking behavior (nonreinforced active lever responding). BLA/DH disconnection following re-exposure to the cocaine-paired context, but not the unpaired context, impaired subsequent drug context-induced cocaine-seeking behavior relative to vehicle or ipsilateral ANI + B/M treatment. Prolonged home cage stay elicited a time-dependent increase, or incubation, of drug-context-induced cocaine-seeking behavior, and BLA/DH disconnection inhibited this incubation effect despite some recovery of cocaine-seeking behavior. Thus, the BLA and DH interact to regulate the reconsolidation of cocaine-related associative memories, thereby facilitating the ability of drug-paired contexts to trigger cocaine-seeking behavior and contributing to the incubation of cocaine-seeking behavior.

Schematics and photomicrographs depicting cannula placement. Arrows mark the most ventral point of injector cannula tracts for cannulae aimed at the BLA and DH on photomicrographs of representative cresyl violet-stained sections. The symbols on the schematics denote the most ventral point of the injector cannula tracts for rats that received unilateral microinfusions of vehicle into the BLA plus VEH into the contralateral DH (open circles), anisomycin (ANI) into the BLA plus baclofen/muscimol (B/M) into the contralateral DH (filled-in, black circles), VEH into the BLA plus VEH into the ipsilateral DH (open triangles), or ANI into the BLA plus B/M into the ipsilateral DH (filled-in, gray triangles). The groups were assigned to remain in their home cages overnight (i.e., 0 d) or for 21 d following the intracranial manipulations. Additionally, control groups received microinfusions following exposure to an unpaired context and remained in their home cages overnight following the intracranial manipulations. Numbers indicate the distance from bregma in mm, according to the rat brain atlas of .

The effects of BLA/DH disconnection on subsequent cocaine seeking are memory reactivation-dependent. (A) Schematic depicting the timeline for Experiment 2. The procedure was identical to that used in Experiment 1 except that rats were exposed to a novel, unpaired context, instead of the cocaine-paired context, before receiving unilateral microinfusions of ANI (62.5 µg/0.5 µL) into the BLA plus B/M (1.0/0.01 mM/0.5 µL) into the contralateral DH, or VEH microinfusions into both brain regions. As in Experiment 1, following the intracranial manipulations, rats received additional extinction training until they reached the extinction criterion (≤25 active lever responses/session on two consecutive days). (B) Mean (±SEM) active lever presses during self-administration (SA; mean of the last three training sessions) and during tests for cocaine-seeking behavior in the extinction context (EXT; the last session preceding the test in the cocaine-paired context) and in the cocaine-paired context (COC-paired). (C) Mean (±SEM) inactive lever presses. (*) Significant difference relative to responding in the extinction context (ANOVA context main effect, P < 0.05).

BLA/DH disconnection following cocaine memory reactivation differentially impairs drug context-induced cocaine-seeking behavior after a 0- or 21-d home cage stay. (A) Schematic depicting the timeline for Experiment 3. The procedure was identical to that used in Experiment 1 except that rats remained in their home cages for 0 d (same groups as in Experiment 1) or 21 d following unilateral microinfusions of ANI (62.5 µg/0.5 µL) into the BLA plus B/M (1.0/0.01 mM/0.5 µL) into the contralateral DH, or microinfusions of VEH into both brain regions. Following the home cage stay, rats received additional extinction training until they reached the extinction criterion (<25 active lever responses/session on two consecutive days). (B) Mean (±SEM) active lever presses during self-administration (SA; mean of the last three training sessions) and during tests of cocaine-seeking behavior in the extinction context (EXT; the last session preceding the test in the cocaine-paired context), and in the cocaine-paired context (COC-paired). (Inset) Mean active lever presses during testing collapsed across context and treatment. (C) Mean (±SEM) inactive lever presses. (D) The time course of active lever responses (mean ± SEM) during the test in the cocaine-paired context. (E) The time course of inactive lever responses (mean ± SEM). (♦) Significant difference relative to the 0-d condition (ANOVA home cage condition main effect, P < 0.05). (*) Significant difference in responding relative to that in the extinction context (ANOVA context simple main effect, P < 0.05). (†) Significant difference relative to VEH treatment (ANOVA treatment simple main effect, P < 0.05). (#) Significant difference relative to all other time intervals (D: 0-d VEH and 21-d ANI + B/M groups, ANOVA time simple main effects, P < 0.05; E, ANOVA time main effect, P < 0.05) or relative to intervals 4 and 6 (D: 21-d VEH group; ANOVA time simple main effect, P < 0.05).